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PROTAC Degradation of Proteins

The brightness and small size of NanoLuc® luciferase and HiBiT peptide make them ideal protein fusion tags that provide sensitive and quantitative methods for monitoring PROTAC™-mediated protein degradation in live cells.

What are PROTACs?

Proteolysis targeting chimeras (shortened to PROTACs) induce selective protein degradation by chemically linking a protein target with an E3 ubiquitin ligase component, which initiates degradation of the protein target via the ubiquitin-proteosome system (UPS). PROTACs are heterobifunctional molecules consisting of two ligands and a short linker. One ligand binds the E3 ligase and the other to the target protein of interest. Because the E3 ligase is part of the ubiquitination complex, the target protein is ubiquitinated and thus, targeted for degradation.

Investigating Key Stages in PROTAC™-Mediated Cellular Protein Degradation

Although methods exist to determine target protein levels, directing the target protein to the proteasome with PROTACs is a multistep process. Interrogating these key steps required for effective PROTAC™-mediated target protein degradation remains a challenge, particularly in cells.

NanoLuc® technologies provide a platform of live-cell assays that can be used to measure real-time degradation kinetics and the key cellular interactions along the UPS that mediate the degradation process. You can even study endogenous protein response when HiBiT is inserted using CRISPR gene editing.

Overview of Live-Cell Based Protein Degradation by PROTACs
This illustration highlights questions about the protein degradation steps in live cells that we can answer with our bioluminescent and energy transfer technologies.

Understanding and Optimizing PROTACs to Study Protein Degradation in Cells

Developing PROTACs that effectively target proteins for degradation can be challenging. Examining only the end result, protein degradation, provides little information about where along the ubiquitin proteasomal pathway the compound failed.

This peer-reviewed article shows how to characterize PROTACs in live cells using endogenous protein tagging and real-time assays that provide better metrics for degradation and examine key cellular protein interactions involved along the pathway. These tools can be used to guide more effective PROTAC™ development.

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NanoLuc Live Cell Assays for PROTAC Protein Degradation

Interested in characterizing PROTACs and targeted protein degradation? Learn More